7-4783682-A-G

Position:

• chr7-4783682-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014855.3(AP5Z1):​c.512-7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,548,868 control chromosomes in the GnomAD database, including 2,858 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (1481 hom., cov: 33)
  • Exomes 𝑓: 0.014 (1377 hom.)
• Consequence: AP5Z1 NM_014855.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003628
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.57

Genes affected

AP5Z1 (HGNC:22197): (adaptor related protein complex 5 subunit zeta 1) This gene was identified by genome-wide screen for genes involved in homologous recombination DNA double-strand break repair (HR-DSBR). The encoded protein was found in a complex with other proteins that have a role in HR-DSBR. Knockdown of this gene reduced homologous recombination, and mutations in this gene were found in patients with spastic paraplegia. It was concluded that this gene likely encodes a helicase (PMID:20613862). [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 7-4783682-A-G is Benign according to our data. Variant chr7-4783682-A-G is described in ClinVar as [Benign]. Clinvar id is 360312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP5Z1	NM_014855.3	c.512-7A>G		splice_region_variant, intron_variant		ENST00000649063.2	NP_055670.1
AP5Z1	NM_001364858.1	c.44-7A>G		splice_region_variant, intron_variant			NP_001351787.1
AP5Z1	XM_047421098.1	c.176-7A>G		splice_region_variant, intron_variant			XP_047277054.1
AP5Z1	NR_157345.1	n.605-7A>G		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2	c.512-7A>G		splice_region_variant, intron_variant			NM_014855.3	ENSP00000497815.1

Frequencies

GnomAD3 genomes AF: 0.0797 AC: 12123 AN: 152098 Hom.: 1475 Cov.: 33

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0321

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00663

Gnomad OTH AF: 0.0675

GnomAD3 exomes AF: 0.0191 AC: 2945 AN: 154268 Hom.: 267 AF XY: 0.0156 AC XY: 1275 AN XY: 81990

Gnomad AFR exome AF: 0.265

Gnomad AMR exome AF: 0.0153

Gnomad ASJ exome AF: 0.00370

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00123

Gnomad FIN exome AF: 0.000539

Gnomad NFE exome AF: 0.00710

Gnomad OTH exome AF: 0.0147

GnomAD4 exome AF: 0.0137 AC: 19151 AN: 1396654 Hom.: 1377 Cov.: 32 AF XY: 0.0125 AC XY: 8631 AN XY: 688626

Gnomad4 AFR exome AF: 0.282

Gnomad4 AMR exome AF: 0.0191

Gnomad4 ASJ exome AF: 0.00371

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00124

Gnomad4 FIN exome AF: 0.000663

Gnomad4 NFE exome AF: 0.00731

Gnomad4 OTH exome AF: 0.0241

GnomAD4 genome AF: 0.0798 AC: 12148 AN: 152214 Hom.: 1481 Cov.: 33 AF XY: 0.0760 AC XY: 5655 AN XY: 74424

Gnomad4 AFR AF: 0.265

Gnomad4 AMR AF: 0.0320

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00663

Gnomad4 OTH AF: 0.0668

Alfa AF: 0.0280 Hom.: 211

Bravo AF: 0.0921

Asia WGS AF: 0.0140 AC: 49 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 48 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 05, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 30, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.22
DANN	Benign	0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000036
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs73305371; hg19: chr7-4823313;